ABSTRACT Through our proposal to join the Pancreatic Cancer Detection Consortium, we aim to drive biomarker development and validation efforts by establishing standardized bio-repositories of high risk individuals and evaluating two innovative molecular imaging approaches to detect pancreatic ductal adenocarcinoma (PDAC) much earlier than is currently possible. We have demonstrated in preclinical imaging studies that contrast-enhanced ultrasound (CEUS) targeted to a kinase insert domain receptor (KDR) can detect sub-centimeter PDAC lesions. Separately, we have developed a new PET tracer that selectively binds to integrin ?v?6, a cell surface receptor that is over-expressed in PDAC. In both approaches, a clinical grade agent with an FDA IND exists to allow first-in-human clinical studies for earlier detection of PDAC. We have formed an experienced scientific team with broad complementary expertise in pancreatology, abdominal radiology, nuclear medicine, statistics, and pancreatic pathology. Our proposal is highly responsive to the PAR in several specific ways. 1) We propose to initiate a phase 3 PRoBE-compliant bio-repository protocol of patients with pancreatic cysts and for high-risk individuals for PDAC identified based on genetic risk factors or family history. Having previously evaluated novel biomarkers in pancreatic cysts and forging collaborations with other centers, our Unit has the experience and capacity to develop and execute standardized multi-center protocols for enrolling these cohorts of patients. 2) We propose two novel molecular imaging trials patients with surgically resectable PDAC. Patients will undergo transabdominal and endoscopic KDR-targeted molecular CEUS imaging, and integrin ?v?6 targeted PET/CT scan before proceeding to surgery. Molecular CEUS and PET/CT imaging results will be correlated to histology and quantitative immunofluorescence between PDAC tissue and adjacent normal and chronic pancreatitis tissue. 3) We will also initiate 2 pilot trials of KDR-targeted molecular CEUS in patients at high risk for developing PDAC. In one study, we will study patients with high risk pancreatic cysts. In another, we will study patients undergoing EUS screening because of genetic risk factors or family history. In all the trials proposed, biospecimens will be collected to support future integration of these imaging approaches with novel circulating biomarkers. The success of these first- in-human trials, and systematic banking of biospecimens, will support further collaborative studies for earlier detection of PDAC.